Colorado drug takes aim at cancer metastasis

Many cancers are relatively harmless at their site of origin, and
it is only when they metastasize to sites like the brain, bones, lungs, and
liver that they become especially dangerous. And so, in addition to stopping
the growth of cancer at its primary site, an ongoing goal of cancer research is
to keep cancer contained – to stop its ability to travel through the body. A
University of Colorado Cancer Center study presented at the American Association
for Cancer Research (AACR) Annual Meeting 2019 offers another step in an
ongoing line of research aimed at exactly that.

Over the course of about a decade, the lab of Heide Ford, PhD, CU
Cancer Center Associate Director and
the David F. and Margaret Turley Grohne Chair in Basic Cancer Research, has
shown that a “transcriptional complex” called SIX1/EYA can gift cells, and even
nearby cells, with the ability to
metastasize. Now the lab, in partnership with the lab of Rui Zhao, PhD, associate
professor in Biochemistry and Molecular Genetics at CU Anschutz Medical Campus,
and with the National Institutes of Health, has identified a compound that
inhibits this action. When the group administered this yet-to-be-named compound
to mouse models of breast cancer, they found that it could, “dramatically suppress breast cancer
associated metastasis,” the study writes.

“A few years ago, we did a small-molecule screen,” Ford says. “Rui [Zhou]
set up a high-throughput screen to identify compounds that would disrupt
SIX1/EYA, and Juan Marugan and his team at the National Chemical Genomics
Center miniaturized the screen and then used their compound libraries to
perform a large-scale screen. We got a bunch of compounds and have been working
to improve them ever since. Our lead compound is looking great – we don’t quite
understand the mechanism of action yet, but in preliminary experiments it dramatically
affects metastasis.”

Like many mechanisms in cancer, one factor making the story of
SIX1/EYA and metastasis especially complex is that these are far from the only
players. First, the Six1 gene itself is
involved in the early development of many of the body’s tissues, including
muscle, auditory, kidney, and craniofacial structures. But after early
development, this gene goes quiet in most adult tissues – unless it is
accidentally paired with EYA after development is complete, which can restart Six1’s action out of context.

The resulting SIX1/EYA pairing is a “transcriptional complex” that
can regulate how often other genes are read and manufactured, effectively
turning up and down gene expression. In the context of cancer, work in the Ford
lab and elsewhere shows that SIX1/EYA is like a volume knob that magnifies
signals transmitted through a network called TGFb. Cells on the receiving end
of this TGFb signal go through a rather dramatic transformation, called an
epithelial-to-mesenchymal transition, or EMT.

Epithelial cells can’t travel through the body. They must remain
anchored to the tissues where they grow; if they become unanchored they die through a process called anoikis, or “the state of being without a home.” But cells with mesenchymal
properties shrug off anoikis and thus can
travel through the body more easily. So, the chain of cause-and-effect goes
something like this: EYA interacts with SIX1; together SIX1/EYA turns on TGFb
signaling (along with additional signaling pathways that promote migration and
invasion), which induces cells and even nearby cells to undergo EMT, making these
EMT cells suddenly able to travel. The result is that cancer cells that should
be stuck in place become able to metastasize.

Ford’s drug stops this chain reaction at the first step, silencing
SIX1/EYA.

“What we think our drug is doing in the tumors is it might be somehow
reversing the EMT, making these cells unable to metastasize,” Ford says. “In
fact, we didn’t have enough drug in this study and so we had to stop
administering it in our animal models after only three weeks, but we measured
metastasis out to nine weeks and it remained almost absent, implying that there
is some sort of long-lasting effect that we wouldn’t have predicted.”

Because SIX1 has no role in most adult tissues, inhibiting its action
should have few side-effects.

“We’ve done toxicity tests in collaboration with Dan Gustafson from
Colorado State University, and a dose that was almost twice what we
administered in our study still had no toxicity we could measure,” Ford says,
noting that lack of toxicity means that in addition to exploring this compound
as a single-agent therapy against cancer metastasis, it may be possible to
combine SIX1/EYA inhibition with other therapies, without increasing toxicity.

In addition to grants from organizations including the National
Institutes of Health and National Cancer Institute, Ford’s lab recently
received a grant from SPARK Colorado, a program meant to speed the translation
of promising basic science into clinical application. Ford hopes to use grant
monies to, “hire chemists to make the drug more soluble, more stable, and more
potent.”

Ford says that, intellectually, she and Dr. Zhao would like to
know more about how, exactly, the drug works, for example knowing whether the
compound is binding to SIX1 or to EYA to inhibit the complex’s action. But she
says that, “If it works, people often don’t care how it works – we may not need to
know the mechanism of action in order to keep moving forward. What we know from
our initial tests, is that our drug inhibited metastasis substantially and so
we hope it could help people not get new metastases.”